p53 isoforms: a major pronostic marker of the metastasis risk

Pierre Roux CRBM/ UMR5237 Montpellier, France

17 May 2016

Invasive modes

Invasion metastases

Primary tumor

Market needs

•  Metastases: cause of cancer death

•  Pronostic marker : prediction of relapse/metastases

•  Therapeutic option: guided by the risk

•  Europe: > 446 000 new cases/y colorectal cancer (CRC), > 463 000 /breast

•  Biomarker in oncology: 15 Md $ in 2013 (35 Md $ in 2018)

•  Urgent need of specific biomarkers of metastasis

A biomarker predicts the risk of recidive

Primary tumor

Biomarker: Personalized therapy

Weak risk: Chemotherapy reduced

High risk: Intensified chemotherapy

Stratification: Targeted theray

Increased survival rate

No biomarker: Colorectal cancer 70% overtreatment

No biomarker: Breast cancer

30% inadequate treatment

1 2 3 4

1 2 3 4 gene

protein

Alternative splicing pre mRNA

mRNA

Isoform A

1 2 3 1 2 3 4 1

Isoform B

Transcription

Alternative splicing generates modified proteins

Alternative splicing as an unexplored program in oncology

Major

3 4

p53: a key role in cancer

Isoforms : modified p53 p53  

•  The most tumor suppressor studied •  The most frequent mutated gene in cancer •  Inactivated function in almost all tumors

Robust biomarker of metastasis risk Unreliable biomarker

                                       

Mutated p53

                                       

                                       331  

                                       

p53γ  p53β  

Δ40p53  

Δ40p53β  Δ40p53γ  

Δ133p53  Δ  133p53β  Δ  133p53γ  

p53  

Alternative Splicing Mutation

A clinical biomarker to predict high risk of relapse in advanced breast cancer

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Breast cancer: 273 tumors •  p53 isoform test:

•  Associated with reduced disease free survival (DFS) and global survival, independently of p53 mutations

•  Predicts high risk of relapse

•  High specificity (93%)

•  Help guide treatment decision-making in selecting which patients should benefit from additional therapy

p53 isoforme: Δ133p53β

Low

High

Opportunity to position p53 isoforms test in breast cancer

Newly diagnosed early invasive breast cancer

Metastatic breast cancer or locally advanced High risk node negative

ER positive (Luminal A)

p53 isoforms test

HER2 positive Triple negative

•  Needs:

•  Luminal A : hormone sensitive cancer (70% of breast tumors)

•  30 % (undetectable) of relapse/metastases in 4 years

•  Predict risk of relapse or treatment failure in Luminal A

•  Adapt treatment strategy

A clinical biomarker to predict high risk of relapse in advanced rectal cancer

•  Needs:

•  Single chemotherpy treatment

•  70 % overtreatment

•  Adapt treatment strategy

•  p53 isoform test:

•  Associated with reduced disease free survival (DFS) and global survival, independently of p53 mutations

•  Predict high risk of relapse

•  High specificity (95%)

•  Help guide treatment decision-making in selecting which patients should benefit from additional therapy

•  All patients may benefit from this test

Rectal cancer

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Low

High

p53 isoform: Δ133p53β

Biomarkers Oncotype DX/Mammaprint p53 isoform Signature Multiplex Monogenic Specificity Weak (63% Oncotype DX) High(93%) Mechanism Non-identifiable Identifiable Associated targeted therapy Impossible Potential Targeting Cost High

(4000 $ Oncotype DX) Reduced (estimated cost < 25 €)

Sample Paraffin (Oncotype DX) / Frozen (Mammaprint)

Paraffin and frozen

Competitive position

•  Colorectal cancer: no test available

•  Breast cancer

Positioning in the value chain developement

Identification Scientific Validation

Pre-Clinical optimization

Clinical trials

Research Clinic Development

Hit Lead

p53 isoform

•  Reliable and robust method (qPCR)

•  High sentitivity and specificity

•  Original mechanism

•  Highly relevant target

•  Meets a market need

•  Needs of ressources

•  Optimization detection kit

•  Design of clinical trials

•  Partnership/ Investors

IP Status

•  Patents : 1.  Bourdon J-C, Fernandez K., Gadea G., Anguille C., Vinot S., and Roux P. Method for testing a subject thought to be predisposed to

having cancer : ∆133p53b : a biomarker of metastatic cancer. Patent EP/30.06.09/EP09305 633.1. 2. Gadea G. Arsic N., Fort P. and Roux P. : Reprogramming method for producing Induced Pluripotent Stem Cells (iPSC). Patent EP/ 30.01.2015/EP15305145. 3. Arsic N., Gadea G., Fort P. and Roux P. : ∆133p53ß and ∆133p53γ are biomarkers of cancer stem cells, Patent EP/30.01.2015/EP15305146.

•  Scope of patents protection: 1.  Method of detection (prediction) 2. Method to assess cancer aggressiveness (pronostic) 3.  Method to determine resistance to therapy (chemoresistance) 4.  Method to screen anti-metastasic compounds (theranostic)

Pierre Roux Véronique Gire

Nikola Arsic Peggy Raynaud Philippe Fort

Emmanuel Vignal Fanny Tomas

Samer Abdallah Anne-Sophie Dume

Team: Dynamic of cancer invasion CRBM Institute, CNRS, Montpellier, France